small molecules

2026-09-16 | Hot Tub Lung: Misdiagnosed Hypersensitivity Pneumonitis Revealing a Mycobacterial Aetiology-A Case Report and Literature Review.

Hot tub lung (HTL) is a rare granulomatous pneumonitis caused by inhalational exposure to Mycobacterium avium complex (MAC)-contaminated hot tub water, with debated pathogenesis encompassing both hypersensitivity and infectious mechanisms. A 66-year-old woman with progressive exertional dyspnea was initially misdiagnosed with non-fibrotic hypersensitivity pneumonitis attributed to pheasant exposure and treated with corticosteroids and mycophenolate without improvement. High-resolution CT demonstrated diffuse centrilobular nodules with air-trapping. Surgical lung biopsy revealed bronchiolocentric non-necrotizing granulomas with rare MAC organisms despite negative bronchoalveolar lavage cultures. Detailed clinical history disclosed daily indoor hot tub use coinciding with symptom onset. Following hot tub cessation and initiation of azithromycin, ethambutol and rifabutin, she ultimately achieved complete clinical and radiologic resolution. HTL represents a heterogeneous spectrum from immune-mediated hypersensitivity to true mycobacterial infection. Persistent interstitial lung disease despite ongoing immunosuppression should prompt a thorough hot tub exposure history and selected patients may require antimycobacterial therapy alongside exposure cessation.

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2026-09-08 | Cough in Interstitial Lung Disease: Current Knowledge and Research Gaps.

Chronic cough is one of the most frequent and burdensome symptoms in patients with interstitial lung disease (ILD), substantially impairing quality of life and, in idiopathic pulmonary fibrosis (IPF), being associated with disease progression. Despite its clinical relevance, the mechanisms underlying cough in ILD remain incompletely understood, and effective therapeutic options are limited. This narrative review summarizes current evidence on the epidemiology, pathophysiology, clinical assessment, and management of cough across the spectrum of ILD. Current data support the concept that ILD-related cough results from a complex interplay between cough reflex hypersensitivity, mechanical distortion of the fibrotic lung, airway and parenchymal inflammation, neural remodeling, and common comorbidities such as gastroesophageal reflux disease and obstructive sleep apnea. Disease-specific mechanisms are also discussed in connective tissue disease-associated ILD, sarcoidosis, and hypersensitivity pneumonitis. We review currently available qualitative and quantitative methods for cough assessment, including patient-reported outcome measures and objective cough monitoring technologies, highlighting their strengths and limitations in clinical practice and research. Finally, we examine established and emerging therapeutic approaches. While antifibrotic therapies have shown limited and inconsistent effects on cough, recent randomized clinical trials provide encouraging evidence for low-dose morphine and extended-release nalbuphine in IPF-associated chronic cough. Nonpharmacological interventions, particularly physiotherapy and speech and language therapy, also demonstrate meaningful benefits. Several novel therapeutic strategies targeting neural and inflammatory pathways are currently under investigation. A better understanding of the mechanisms driving cough in ILD, together with standardized assessment tools and adequately powered clinical trials, will be essential to develop effective, disease-specific treatments for this disabling symptom.

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2026-08-27 | The Therapeutic Efficacy of Inhaled Vitamin D3 Metabolites Initiated During the Acute Phase of Hypersensitivity Pneumonitis: An In Vivo Study.

Our earlier studies have revealed the beneficial impact of vitamin D3 (VD3) metabolites on the development of pulmonary fibrosis in a murine model of hypersensitivity pneumonitis (HP). Despite the discovery of the great antifibrotic potential of both the bioactive form of VD3, 1,25(OH)2-VD3 and its direct precursor, 25(OH)-VD3, study designs based on the co-administration of VD3-metabolites and fibrosis-inducers do not reflect the clinical situation. Thus, the presented study aims to examine the effectiveness of therapeutic interventions based on the mentioned inhalations, initiated during the acute phase of HP at the first signs of pulmonary fibrosis. The research was performed using VD3-deficient mice with HP, while VD3-sufficient mice were used as the main control. The data were collected after 28 days of daily exposure of the mice to a fibrosis-inducer (an antigen of Pantoea agglomerans, a well-known etiological factor in HP), with 25(OH)-VD3 or 1,25(OH)2-VD3 administered daily during the last 14 days of the experiment. The effect of the intervention was monitored by whole-body plethysmography, histological assessment, flow cytometry, RealTime-PCR, and ELISA. Treatment with VD3 metabolites initiated during the acute phase of HP alleviated the disease courses and restored respiratory function, thanks to inhibition of pathological extracellular matrix deposition, immune-cell infiltration of lung parenchyma, profibrotic cytokine production, and EMT progression. Despite the discovery of the beneficial features of the investigated VD3-based therapies, none of them caused full recovery in mice with HP. Nevertheless, after verification in additional animal models and a deeper understanding of the underlying molecular mechanisms, the identified beneficial features of the investigated metabolites have the potential to serve as a foundation for future therapies for HP fibrosis.

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2026-08-24 | Successful immunosuppressive treatment of hypersensitivity pneumonitis secondary to lycoperdonosis in a dog.

A 7-year-old neutered male Cocker Spaniel with unrestricted access to rural land presented for progressive lethargy, tachypnea, and cough. Thoracic radiographs showed an unstructured interstitial pattern. Fine-needle aspirate (FNA) lung cytology identified pyogranulomatous inflammation with intralesional mushroom spores. Acute hypersensitivity pneumonitis (HP) was suspected, and treatment was initiated with oxygen supplementation and an immunosuppressive dosage of corticosteroid. Thoracic computed tomography (CT) and bronchoalveolar lavage (BAL) were performed on day 6, month 2, and year 1 to track therapeutic response and assess architectural changes. Clinical signs guided prednisone tapering and discontinuation. One year later, thoracic CT and BAL confirmed re-exposure to mushroom spores with mild persistent inflammation and CT changes suggestive of mixed parenchymal and small airway disease despite absent clinical signs. This case report emphasizes the importance of rapid identification of pulmonary mushroom spores for prompt immunosuppressive treatment. Unlike prior reports of lycoperdonosis with acute, fulminating, and generally fatal outcomes, this dog developed chronic HP.

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2026-07-16 | Laboratory and field performance of 2-(thiocyanomethylthio)benzothiazole against fast-growing nontuberculous mycobacteria found in metalworking fluid.

Uncontrolled, fast-growing nontuberculous mycobacteria (NTM) in metalworking fluids (MWFs) can cause dermal lesions, hypersensitivity pneumonitis, and other health complications in exposed metalworkers. Although biocides are routinely used to control microbial growth in MWF, they are often ineffective because they are unsuitable for the physical or chemical conditions of the system, added infrequently, or ineffective against the microorganisms present. Given the increasing concern for NTM in industrial settings, there is a growing need for MWF-compatible (i.e., nonoxidizing) biocides that are effective against NTM. Here, we evaluated the efficacy of four nonoxidizing biocides against fast-growing NTM species in water-based MWF. Results from a 72-hr laboratory challenge indicated that biocides containing 2-(thiocyanomethylthio)benzothiazole (TCMTB), commonly used as a fungicide, were most effective at controlling Mycobacterium chelonae, M. fortuitum, and field and laboratory strains of M. immunogenum. In subsequent field trials at nine MWF plants where workers had reported symptoms of dermal and lung illnesses, TCMTB consistently reduced viable NTM counts, as measured through both culture-based assays and microscopy. However, dosages needed to be increased two- to four-fold relative to the laboratory experiments to control NTM populations in systems with established biofilms. Due to the observed success of TCMTB against NTM in field context, the manufacturing plants involved in this study continued regular application of TCMTB as a preventative treatment. No additional outbreaks were observed throughout our follow-up period, which, in several cases, spanned approximately 10 years. The results suggest that TCMTB may provide an efficacious method for treating and preventing NTM contamination in MWF systems. Future studies should explore the mechanism of action of the sulfur-rich chemical structure of TCMTB to potentially guide the development and synthesis of related compounds with anti-NTM properties. One sentence summary 2--(thiocyanomethylthio)benzothiazole kills fast-growing nontuberculous mycobacteria, including Mycobacterium immunogenum, and prevents worker infections based on laboratory, field trial, and long-term (6-10 years) industrial studies.

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proteins

2025-09-27 | Cardiotrophin-1 as a predictor of critical COVID-19, mortality, and persistence of pulmonary fibrosis after the acute phase of infection.

Pulmonary fibrosis remains a long-term complication in some COVID-19 recovered patients, particularly in those who suffered from severe disease. Cardiotrophin-1 (CT-1) is an antiapoptotic cytokine related with the progression of fibrotic disease in heart and kidney. This study examines the association between CT-1 plasma levels, COVID-19 severity, and post-COVID pulmonary fibrosis. CT-1 levels were analyzed in patients with asymptomatic/mild (n = 33), severe (n = 39), and critical (n = 57) COVID-19, as well as in those with post-COVID pulmonary fibrosis. Elevated CT-1 levels were associated with a higher risk of severe disease, mortality, and persistent pulmonary fibrosis even a year after discharge. Furthermore, CT-1 was associated with non-COVID-19-related pulmonary fibrosis, suggesting a broader role of this cytokine in chronic lung diseases. These findings propose CT-1 as a potential biomarker and therapeutic target for pulmonary fibrosis and provide new insights for its role in chronic respiratory conditions, such as idiopathic pulmonary fibrosis (IPF), post-COVID interstitial lung disease or chronic hypersensitivity pneumonitis.

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2025-03-12 | A human histidyl-tRNA synthetase splice variant therapeutic targets NRP2 to resolve lung inflammation and fibrosis.

Interstitial lung disease (ILD) consists of a group of immune-mediated disorders that can cause inflammation and progressive fibrosis of the lungs, representing an area of unmet medical need given the lack of disease-modifying therapies and toxicities associated with current treatment options. Tissue-specific splice variants (SVs) of human aminoacyl-tRNA synthetases (aaRSs) are catalytic nulls thought to confer regulatory functions. One example from human histidyl-tRNA synthetase (HARS), termed HARSWHEP because the splicing event resulted in a protein encompassing the WHEP-TRS domain of HARS (a structurally conserved domain found in multiple aaRSs), is enriched in human lung and up-regulated by inflammatory cytokines in lung and immune cells. Structural analysis of HARSWHEP confirmed a well-organized helix-turn-helix motif. This motif bound specifically and selectively to neuropilin-2 (NRP2), a receptor expressed by myeloid cells in active sites of inflammation, to inhibit expression of proinflammatory receptors and cytokines and to down-regulate inflammatory pathways in primary human macrophages. In animal models of lung injury and ILD, including bleomycin treatment, silicosis, sarcoidosis, chronic hypersensitivity pneumonitis, systemic sclerosis, and rheumatoid arthritis-ILD, HARSWHEP reduced lung inflammation, immune cell infiltration, and fibrosis. In patients with sarcoidosis, efzofitimod treatment resulted in down-regulation of gene expression for inflammatory pathways in peripheral immune cells and stabilization of inflammatory biomarkers in serum after steroid tapering. We demonstrate the immunomodulatory activity of HARSWHEP and present preclinical data supporting ongoing clinical development of the biologic efzofitimod based on HARSWHEP in ILD.

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2024-11-15 | T cell receptor sharing in hypersensitivity pneumonitis

Abstract Hypersensitivity pneumonitis (HP) is characterised by an excessive pulmonary T cell response in susceptible individuals after exposure to inhaled antigens. The most effective treatment for the condition is antigen avoidance, but in most cases an antigen cannot be identified. Profiling antigen-specific T cell responses may form the basis of a strategy to identify causative antigens of the disease. We used public RNA sequencing data and reconstructed T cell receptor (TCR) repertoires from blood and bronchoalveolar lavage samples from patients with HP, idiopathic pulmonary fibrosis and healthy controls. After excluding TCR sequences likely to be related to common microbial exposures in patients with HP, we identified TCRs shared between patients with shared human leukocyte antigen alleles, indicating patients likely to have a common causative antigen. We also identified clusters of TCRs containing identical and similar TCR clones in individual patients that are plausibly related to the causative antigens in those patients. These results establish the feasibility of profiling TCR repertoires to identify antigens in HP.

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2023-12-04 | Eosinophil Phenotypes Are Functionally Regulated by Resolvin D2 during Allergic Lung Inflammation.

Eosinophils (Eos) reside in multiple organs during homeostasis and respond rapidly to an inflammatory challenge. Although Eos share chemical staining properties, they also demonstrate phenotypic and functional plasticity that is not fully understood. Here, we used a murine model of allergic lung inflammation to characterize Eos subsets and determine their spatiotemporal and functional regulation during inflammation and its resolution in response to resolvin D2 (RvD2), a potent specialized proresolving mediator. Two Eos subsets were identified by CD101 expression with distinct anatomic localization and transcriptional signatures at baseline and during inflammation. CD101low Eos were predominantly located in a lung vascular niche and responded to allergen challenge by moving into the lung interstitium. CD101high Eos were predominantly located in bronchoalveolar lavage (BAL) and extravascular lung, only present during inflammation, and had transcriptional evidence for cell activation. RvD2 reduced total Eos numbers and changed their phenotype and activation by at least two distinct mechanisms: decreasing interleukin 5-dependent recruitment of CD101low Eos and decreasing conversion of CD101low Eos to CD101high Eos. Collectively, these findings indicate that Eos are a heterogeneous pool of cells with distinct activation states and spatiotemporal regulation during resolution of inflammation and that RvD2 is a potent proresolving mediator for Eos recruitment and activation.

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2023-10-27 | Impact of antigen identification on transplant free survival in interstitial lung disease.

Antigen identification impacts diagnosis as well as prognosis in patients with hypersensitivity pneumonitis. An antigen may also be present in other etiologies of interstitial lung disease, however it is unknown whether identification impacts survival. We evaluated a retrospective cohort in order to determine if antigen identification affects transplant free survival in patients with hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, connective tissue disease interstitial lung disease, and interstitial pneumonia with autoimmune features. Only patients with definite or high probability of hypersensitivity pneumonitis by American Thoracic Society guidelines were included in the analysis. Transplant free survival was improved with antigen identification in patients with hypersensitivity pneumonitis but not in patients with idiopathic pulmonary fibrosis, connective tissue disease interstitial lung disease, and interstitial pneumonia with autoimmune features. Our study suggests that removal of identified antigen in interstitial lung diseases other than hypersensitivity pneumonitis may not be impactful. Additionally, it further suggests that definitive diagnosis of hypersensitivity pneumonitis with bronchoalveolar lavage and transbronchial biopsy may be beneficial prior to recommending antigen removal.

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antibodies

2026-09-28 | Immunological endotypes and fibrotic biomarkers in patients with advanced fibrotic hypersensitivity pneumonitis undergoing lung transplantation

Abstract Hypersensitivity pneumonitis (HP) is an interstitial lung disease, with approximately 40% of patients progressing to pulmonary fibrosis. The aim of this study was to characterize the immunological profile of patients with advanced fibrotic HP undergoing lung transplantation. A cross-sectional study was conducted including 19 patients with fibrotic HP, 10 patients with idiopathic pulmonary fibrosis (IPF), and 8 healthy donors as controls. Lung tissue and pre-transplant serum samples were collected. Levels of Th1-, Th2-, Th17-, and pro-inflammatory cytokines, as well as the fibrotic biomarkers Krebs von den Lungen-6 (KL-6) and mucin 16 (MUC16), were analyzed in both tissue and serum samples. Fifty percent of HP patients exhibited a pronounced Th2-high profile, characterized by elevated IL-5, IL-6, IL-1β, IL-8, G-CSF, and MCP-1 compared with Th2-low HP patients. Th2-high HP patients also showed increased IL-7, IL-12p70, TNF-α, IL-13, GM-CSF and IL-17A, while Th2-low patients had higher IL-2, IL-13, GM-CSF and IL-23 relative to healthy controls. KL-6 expression was higher in HP lung tissue than in healthy controls, and serum KL-6 levels were elevated in HP compared with IPF, particularly in Th2-low patients. MUC16 tissue expression was maximal in IPF patients and exceeded that of Th2-high HP patients, although serum levels did not differ between groups. Cytokine levels in serum were largely comparable, except for IL-10, which was higher in Th2-high HP patients versus IPF. Fibrotic HP appears to involve two distinct immunological profiles: Th2-high and Th2-low profiles. Th2-high patients may exhibit heightened adaptive immune activation and increased granulocyte recruitment, suggesting that immune endotyping may provide insights into disease pathogenesis and potentially inform personalized therapeutic strategies.

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2026-08-05 | Does bronchoalveolar lavage lymphocytosis predict prognosis in fibrotic hypersensitivity pneumonitis, and is this relationship influenced by low-dose immunomodulatory therapy at the time of BAL?

Bronchoalveolar lavage (BAL) lymphocytosis is associated with improved prognosis in fibrotic hypersensitivity pneumonitis (fHP), although its prognostic value is unclear in patients receiving immunomodulatory treatment. We investigated whether treatment tapered to the lowest tolerated level at the time of BAL modifies associations with disease severity, one-year lung function, and transplant-free survival. We analysed 247 fHP patients undergoing BAL, including 162 untreated and 85 receiving immunomodulatory therapy at the time of BAL. Associations between BAL lymphocytosis and baseline composite physiologic index (CPI), one-year CPI change, and transplant-free survival were assessed using multivariable flexible parametric survival models incorporating treatment status and interaction terms, adjusted for covariates. Mean age was 63 years, 43% male, 37% ever-smokers. Treated patients at the time of BAL were younger, with more severe disease (higher CPI). Mean BAL lymphocyte percentages were similar between two groups and inversely associated with baseline CPI in both. Higher BAL lymphocyte% were associated with more favourable CPI change in both untreated (-1.7 points per 10% increase; 95%CI -2.5--0.8, p < 0.0001) and treated patients at BAL (-2.0 points; 95% CI -3.1--0.9, p < 0.0001), with no treatment-by-BAL lymphocyte interaction (p = 0.64). Higher BAL lymphocyte% independently predicted lower mortality both in untreated (HR 0.87 per 10% increase, p = 0.036) and treated patients at the time of BAL (HR 0.78, p = 0.025), with no treatment-by-BAL lymphocyte interaction (p = 0.39). BAL lymphocytosis was associated with less severe disease, favourable one-year CPI change and better survival, irrespective of background immunomodulatory therapy.

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2026-05-03 | Real-world evidence on hospitalization, infection, and vascular outcomes among interstitial lung disease subtypes.

Interstitial lung diseases (ILDs) consist of idiopathic pulmonary fibrosis (IPF) and non-IPF ILDs. While pulmonary complications in IPF are relatively well-studied, there is a need for research on non-IPF ILDs, including connective tissue disease-associated ILDs (CTD-ILDs), and non-pulmonary outcomes of ILDs. We compare hospitalization, infection, and pulmonary/cardiac vascular event outcomes in patients with various ILDs. We used data from 82 healthcare organizations between 2014 and 2023 on the TriNetX Research Network. In addition to IPF, we included patients with rheumatoid arthritis (RA)-ILD, systemic sclerosis (SSc)-ILD, myositis-ILD, hypersensitivity pneumonitis (HP) and pulmonary sarcoidosis. We employed propensity score matching (PSM) and assessed outcomes, including hospitalization, infection, and pulmonary/cardiac vascular events within one year of diagnosis. A total of 66,771 patients met the inclusion criteria, with 15,228 diagnosed with IPF and 51,543 with non-IPF ILDs. Anti-fibrotic agents were used in 30.4% of IPF patients. IPF patients had higher risks of hospitalization, cytomegalovirus disease, aspergillosis, and pulmonary/cardiac vascular event compared to those with non-IPF ILDs. Within CTD-ILDs, RA-ILD was associated with increased risks of sepsis, bacteremia, and pneumonia, while SSc-ILD had higher risks of pulmonary vascular events. Myositis-ILD showed elevated risks of hospitalization and mortality compared to RA-ILD, whereas patients with HP and pulmonary sarcoidosis experienced more favorable outcomes. We identified distinct risk profiles across ILD subtypes, with increased infection risks in RA-ILD and heightened pulmonary/cardiac vascular event risks in SSc-ILD and IPF. These findings emphasize the need for targeted surveillance/management strategies for different ILD subtypes.

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2026-05-01 | C104-01 Utility of Radiographic Fibrosis as Theragnostic Marker for Immunomodulatory Therapy in Hypersensitivity Pneumonitis

Abstract Background Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) caused by exposure to inhaled allergens, triggering an immune-mediated “inflammatory response” with subsequent lung injury and often resulting in lung fibrosis. It is widely accepted that the first-line therapy in HP is antigen avoidance, however, there are still meaningful decisions regarding treatment choice when patients experience progression. Treatment selection in chronic hypersensitivity pneumonitis (HP) remains empiric due to a lack of randomized trial data and clinicians lack any validated markers that meaningfully identify those HP patients most likely to positively respond to immunomodulation versus those who are most likely to benefit from an antifibrotic approach. This study aims to address that gap by evaluating the association between forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) response to immunomodulation and the visual extent of fibrosis on pre-treatment computed tomography (CT) scans in patients with HP. Methods The retrospective cohort study included 108 patients with HP from two ILD referral centers who received ≥3 months of immunomodulatory therapy (prednisone, azathioprine, mycophenolate mofetil and rituximab) and had pre- and post-treatment pulmonary function tests (PFTs) and pretreatment CT for review. Fibrosis extent was classified as ≥ 10% or &lt; 10% based on blinded thoracic radiologist interpretations. Linear spline mixed-effects models were used to estimate FVC and DLCO % predicted trajectory before and after immunomodulation, with patients serving as their own controls. The primary analysis evaluated whether fibrosis extent modified the association between immunomodulation and lung function trajectory. Results Overall, immunomodulation was associated with a modest FVC improvement at 12-months (+2.63%, 95% CI: 0.72 to 4.54; p &lt; 0.01) across the entire cohort. Among patients with &lt;10% fibrosis, immunomodulation was associated with improvements in both FVC (+5.83%, p &lt; 0.01) and DLCO (+13.9%, p &lt; 0.01). In contrast, no improvement in FVC (+0.81%, p = 0.42) or DLCO (-4.3%, p = 0.17) was observed in patients with ≥10% fibrosis at 12-months (Figure). Baseline demographics, smoking history, and antigen identification status were similar between fibrosis groups. Conclusion Visual fibrosis extent is associated with differential pulmonary function response to immunomodulatory therapy in chronic HP. Patients with limited fibrosis experienced improved pulmonary function compared to those with greater radiographic fibrosis. These findings may support the use of fibrosis extent as a clinical tool for treatment stratification and highlight the need for prospective trials to validate radiographic markers in guiding HP management. This abstract is funded by: None

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2026-03-01 | 648: USE OF STEROID-SPARING AGENTS IN HYPERSENSITIVITY PNEUMONITIS-RELATED INTERSTITIAL LUNG DISEASE

Introduction: Hypersensitivity pneumonitis-related interstitial lung disease (HP-ILD) is an immune-mediated lung condition caused by repeated inhalation of environmental antigens, leading to inflammation and, in some cases, fibrosis. It is categorized as fibrotic or non-fibrotic, with fibrotic HP-ILD linked to worse outcomes. Antigen avoidance remains key, but corticosteroids are often required when imaging or pathology shows inflammation. In chronic disease, steroid-sparing agents like mycophenolate mofetil (MMF) and azathioprine (AZA) may help preserve lung function, though their efficacy may be reduced in patients with telomere dysfunction. Rituximab has shown benefit in refractory disease, and lung transplant may be considered in advanced cases. Acute exacerbations can present with worsening dyspnea, cough, fever, and increased oxygen needs. While steroids are first-line, intravenous immunoglobulin (IVIg), with immunomodulatory properties, has shown benefit in fibrotic ILD flares. Description: A 73-year-old man with biopsy-confirmed fibrotic HP-ILD and coronary artery disease presented with cough, dyspnea, and flu-like symptoms. He was initially treated for presumed pneumonia with antibiotics and IV methylprednisolone (60 mg daily). His condition worsened, requiring higher oxygen support. An acute HP-ILD exacerbation was diagnosed, and he was transferred to a step-down unit. Treatment was escalated to IV methylprednisolone (125 mg twice daily) and IVIg (5 g daily for three days). The patient improved, with decreased oxygen needs and symptom resolution. Infections were ruled out. He was discharged on oral prednisone (60 mg twice daily) with plans to assess telomere length and start MMF if telomeropathy was absent. Discussion: IVIg may serve as a useful adjunct in managing acute HP-ILD exacerbations requiring high oxygen support. Its immunomodulatory actions complement therapies targeting T-cell (MMF, AZA) and B-cell (rituximab) pathways. Corticosteroids remain the foundation of treatment, but steroid-sparing agents offer long-term disease control, particularly in patients without telomeropathy. Though evidence for IVIg is limited, this case supports its potential role. Further research is needed to clarify its efficacy, dosing, and integration into long-term care plans.

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cell therapies

2026-03-26 | A novel agarose-free, standardized generation and versatile ECM characterization of decellularized scaffolds from normal and fibrotic human lung tissue.

The extracellular matrix (ECM) is a key regulator of tissue homeostasis and remodeling in interstitial lung diseases (ILD) such as idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (FHP). Decellularized lung scaffolds provide a physiologically relevant platform for studying cell-matrix interactions but generating structurally intact scaffolds from fibrotic human lungs remains challenging. Many existing protocols struggle with either insufficient removal of the cells or significant disruption of certain ECM components. In addition, all of them rely on agarose-embedding for the production of thin lung slices. Tissue samples were decellularized using apoptosis inducers (Camptothecin, Raptinal) and a mild detergent (SB-10). Standardized decellularized lung scaffolds (SDLS) were generated using a gelatin-based temporary cutting support structure, which is completely removable prior to recellularization. Decellularization and preservation of the ECM was validated by DAPI nuclear counts and semi-quantitative image analysis of collagen (picro-sirius red under polarization) and elastin (elastic Verhoeff-Van Gieson (EVG)). For functional testing, SDLS were repopulated with primary human lung fibroblasts (CD90+CD31-CD45-) and assessed for colonization, viability (WST-1 assay), and cytotoxicity (LDH assay). The protocol removed all nuclei (>99.8%) in both fibrotic and non-fibrotic lung tissue while preserving structural integrity and the major ECM components (collagen and elastin). The novel semi-quantitative analysis proved to be accurate and versatile for the analysis of multiple ECM components within one sample. Overall, both Collagen (fresh 15.5% ± 4.3 vs. decellularized 16.7% ± 4.4) and elastin (fresh 10.0% ± 3.7 vs. decellularized 9.8% ± 3.4) remained stable post-decellularization. Fibroblasts successfully colonized SDLS, with non-fibrotic scaffolds showing pronounced contraction, whereas fibrotic scaffolds retained their dimensions. Even though fibroblasts seeded on SDLS showed significantly lower viability than those seeded on plastic plates, cytotoxicity 1 day after repopulation was not increased and remained acceptable. We present a reproducible, agarose-free, apoptosis-assisted method for the generation of residue-free and standardized decellularized lung scaffolds from normal and fibrotic human tissue. The novel semi-quantitative histological analysis allows the investigation of multiple ECM components from a single sample. The SDLS platform preserves key ECM components and supports controlled recellularization enabling physiologically relevant studies of matrix-cell interactions and therapeutic screening in ILD models.

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2025-11-27 | Ethylbenzene Exposure and Bronchoalveolar CD4/CD8 T Cells in Hypersensitivity Pneumonitis Development and Clinical Outcome.

Background: Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) characterized by inflammation of the lung parenchyma, alveoli and bronchioles induced by inhalation of organic compounds. Bird-related-HP (BRHP) is the most common type of HP, occurring in susceptible people in regular contact with birds, although a genetic susceptibility is unclear. This study investigates the impact of environmental volatile organic compounds (VOCs) on the development of HP and other pulmonary diseases, and their relationship with pulmonary inflammatory cell composition and patient outcomes. Methods: Geospatial environmental levels of VOCs (benzene, toluene, ethylbenzene, m,p-xylene and o-xylene) in patients' homes were related to bronchoalveolar lavage (BAL) leukocyte profiles analyzed by flow cytometry of 1515 patients with different lung diseases in the region of Murcia (southeastern Spain). Results: Ethylbenzene levels over the threshold limit of 10 µg/m3 (EB10) were associated with HP (23.9% vs. 15.2%, p < 0.05). A strong association with HP was observed in patients in contact with birds living in areas with EB10 (63.0% vs. 27.4%, p < 0.001). Linear regression analysis showed that age (B = -0.058, p < 0.012), smoking (B = -0.125, p < 0.001), bird contact (B = 0.275, p < 0.001) and EB10 (B = 0.109, p < 0.001) were independent variables associated with HP. In HP patients, BAL CD4/CD8-ratio > 1.5 was associated with shorter overall survival (8.9 years vs. not-reached, p < 0.011), probably due to lower CD8+ T-lymphocyte counts observed in HP fibrotic patients (11.65 ± 2.8% vs. 23.6 ± 2.9%, p = 0.008) and in those who died during follow-up (10.0 ± 1.9% vs. 23.8 ± 2.7%, p = 0.012), suggesting a protective role for CD8+ T cells. Conclusions: High environmental ethylbenzene is strongly associated with BRHP. CD8+ T-lymphocytes could have a protective role in HP, preventing fibrosis and increasing overall survival.

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2025-05-01 | Cross-systems Transcriptomics Uncovers Molecular Endotypes of Hypersensitivity Pneumonitis

Abstract RATIONALE: Hypersensitivity pneumonitis (HP) is an interstitial lung disease triggered by immune responses to inhaled environmental antigens, with diverse clinical manifestations and prognoses, currently clinically classified as fibrotic and non-fibrotic HP. We hypothesized that whole blood transcriptomics would identify HP endotypes with differing traits and outcomes, and findings would be confirmed across multiple cohorts and organ system datasets. METHODS: We performed a retrospective analysis of whole blood RNA-seq data from the Pulmonary Fibrosis Foundation Patient Registry (PFFr, N=126) and University of California Davis (UCD, N=40), and peripheral blood mononuclear cells (PBMCs) RNA-seq from National Jewish Health (NJH, N=37), independent of clinical traits. The bifurcation structure of each cohort was reconstructed with dimensionality reduction using R-package “DDRTree”. HP-classifier was developed by Recursive-Feature-Elimination (RFE) using R-package “caret’. HP endotypes were confirmed in RNA-seq of lung biopsy, scRNA-seq of bronchoalveolar lavage (BAL) and PBMCs in Gene Expression Omnibus database. RESULTS: Two subclasses were revealed in PFFr cohort (Fig.1A), stratified into ‘Major’ (88 patients) and ‘Minor’ (38 patients) with 9,817 differentially expressed genes (adjusted p-value&lt;0.05) between them. The Minor subclass exhibited lower baseline forced vital capacity (FVC) %predicted (p=0.002), greater FVC-decline over 12-months (Fig.1C), and worse transplant-free survival (Fig.1D). Cross-validation of PFF sub-classification using a 40-gene HP-classifier via RFE demonstrated 94.7% sensitivity and 98.9% specificity. Machine-learning with HP-classifier identified 13 patients as Minor in UCD and NJH test cohorts, with 12 confirmed through intrinsic bifurcation. Pathway analysis revealed activation of neutrophil-mediated immunity in the Minor endotype of PFF and UCD cohorts, while the Major endotype exhibited adaptive immune activation across PFF, UCD and NJH cohorts (Fig.1B). Pseudo-bulk analysis of scRNA-seq data of BAL samples from a publicly available cohort identified 6 Minor and 3 Major samples. Pseudo-bulk analysis of PBMCs scRNA-seq data identified 15 Minor samples with increased CD14+ monocytes, while 22 Major samples had more CD8_GZMH/K-high T-cells. Pathway analysis of BAL and PBMCs confirmed neutrophil activation in the Minor and natural killer cell-mediated immunity in the Major endotype. Additionally, dimensionality reduction of the 26 lung biopsies in GSE150910 revealed 5 Minor samples with activated extracellular matrix and 21 Major samples with T-cell activation. Conclusions: Blood transcriptomics revealed two distinct fibrotic HP endotypes, each exhibiting unique molecular, cellular and clinical characteristics. Such molecular endotyping may further enable mechanistic differences for targeted development of cell-specific therapies tailored to each endotype. Further research with larger cohorts is necessary to explore the clinical implications of HP endotypes.

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2025-04-02 | Flavor chemicals in vaping products induce pulmonary dendritic cell maturation.

Vaping products contain numerous flavor chemicals that are known immunological sensitizers associated with the elicitation of immune-mediated hypersensitivity responses. Therefore, we investigated the immune response associated with sensitizing flavor chemicals in vaping liquids and focused on dendritic cell maturation as it is a crucial early cellular event of the sensitization immunological cascade. Bone marrow-derived dendritic cells (BMDDCs) were used to assess induction of dendritic cell maturation upon treatment with unique flavor vaping liquids and aerosol condensates. Female BALB/c mice were exposed 2 h/day for 4 days to nicotine-free vaping aerosols containing a mixture of citral, cinnamaldehyde, dihydrocoumarin, and vanillin. In vitro experiments indicate that cinnamaldehyde and citral, but not vaping liquid solvents, dihydrocoumarin and vanillin, are capable of inducing BMDDC maturation. In vivo, we observed an increase in the expression of maturation marker MHC class II (MHCII) on conventional dendritic cells (cDCs) in the lung tissue of mice exposed to flavored vaping aerosols compared with exposure controls. Maturation was specifically observed on CD11b+ cDCs and not CD103+ cDCs. No significant changes were observed for macrophages, neutrophils, B and T lymphocytes in the lung tissue, and bronchoalveolar lavage. Also, we found that regulatory T lymphocytes had decreased expression of CD25 in mice exposed to flavored vaping aerosols compared with exposure controls. These findings indicate that flavored chemicals can lead to rapid dendritic cell maturation in vitro and in vivo, representing an early cellular event related to respiratory sensitization and pulmonary disease.NEW & NOTEWORTHY Current research on vaping do not report major impact on cellular immune response. However, our findings support that flavored vaping aerosol exposure can lead to rapid modulation of dendritic cells and regulatory T lymphocytes in the lungs and extrapulmonary location. Although our findings were obtained in acute settings, they entertain the possibility that chronic exposure to vaping aerosols could progressively trigger the immunological cascade responsible for the development of serious lung diseases resembling hypersensitivity pneumonitis.

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2025-01-23 | Immunopathological characteristics and therapeutic effects of UC-MSCs in a pigeon breeder's lung mouse model.

Hypersensitivity pneumonitis (HP), including pigeon breeder's lung (PBL), often progresses from acute inflammation to fibrosis, impairing lung function and limiting targeted therapeutic strategies. Mechanistic studies on PBL progression are limited by the lack of preclinical animal models and a predominant focus on patient data. This study explores the immunopathological characteristics of all stages of PBL in mice and evaluates the therapeutic potential of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) during the non-fibrotic stage. PBL models are created in A/J mice through tracheal instillation of pigeon dropping extract (PDE) protein powder. Different doses (0.4 × 10 6, 0.8 × 10 6, and 1.6 × 10 6 cells per animal) and frequencies (1-2 times) are administered to the model. The immunopathological characteristics of PBL and the therapeutic effects of UC-MSCs are assessed using micro-CT, pulmonary function, histopathology, cell counts in BALF, HYP levels, inflammatory factor levels, immunohistochemistry, and fibrosis marker expression in lung tissues. The results show that PDE exposure consistently impairs pulmonary function and increases the levels of inflammation and fibrosis markers as the disease progresses. Model mice experience non-fibrotic stages (acute inflammation) from days 0-36, mild fibrosis from days 37-77, and severe fibrosis from day 78 onwards. UC-MSCs, particularly at the highest dose (1.6 × 10 6 cells), effectively treat non-fibrotic PBL by improving pulmonary function (lung ventilation area recovers) and reducing inflammation and fibrosis. This study successfully establishes PBL mouse models reflecting both the acute (inflammatory) and chronic (fibrotic) stages, and UC-MSCs have the potential to delay fibrosis, providing new therapeutic options for PBL and other inflammation-induced lung fibrotic diseases.

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2025-08-19 | Spontaneous Resolution of Miliary Pulmonary Nodules Following Intravesical Bacillus Calmette-Guérin (BCG) Therapy: A Case Report and Literature Review.

Intravesical Bacillus Calmette-Guérin (BCG) immunotherapy is a well-established treatment for non-muscle-invasive bladder cancer. Although it is typically associated with local irritative symptoms, rare systemic and pulmonary complications can occur, including hypersensitivity pneumonitis and miliary tuberculosis. We report the case of a 70-year-old man who developed diffuse miliary pulmonary micronodules and ground-glass opacities after his 12th BCG instillation. Despite imaging findings suggestive of disseminated infection, the patient remained clinically stable, without fever, hypoxia, or systemic deterioration. Bronchoalveolar lavage cultures were negative for Mycobacterium bovis. A shared decision was made to withhold antimycobacterial therapy and monitor closely. Follow-up imaging revealed spontaneous improvement without treatment. This case underscores that observation may be appropriate in selected stable patients without systemic signs of infection. Careful clinical assessment and individualized management are essential to avoid unnecessary therapy and ensure patient safety.

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2023-06-28 | The Presence of T Allele (rs35705950) of the MUC5B Gene Predicts Lower Baseline Forced Vital Capacity and Its Subsequent Decline in Patients with Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis (HP) is an exposure-related interstitial lung disease with two phenotypes-fibrotic and non-fibrotic. Genetic predisposition is an important factor in the disease pathogenesis and fibrosis development. Several genes are supposed to be associated with the fibrosing cascade in the lungs. One of the best-recognized and most prevalent is the common MUC5B gene promoter region polymorphism variant rs35705950. The aim of our study was to establish the frequency of the minor allele of the MUC5B gene in the population of patients with HP and to find the relationship between the MUC5B promoter region polymorphism and the development of lung fibrosis, the severity of the disease course, and the response to the treatment in patients with HP. Eighty-six consecutive patients with HP were tested for the genetic variant rs35705950 of the MUC-5B gene. Demographic, radiological, and functional parameters were collected. The relationship between the presence of the T allele and lung fibrosis, pulmonary function test parameters, and the treatment response were analyzed. The minor allele frequency in the study group was 17%, with the distribution of the genotypes GG in 69.8% of subjects and GT/TT in 30.2%. Patients with the GT/TT phenotype had significantly lower baseline forced vital capacity (FVC) and significantly more frequently had a decline in FVC with time. The prevalence of lung fibrosis in high-resolution computed tomography (HRCT) was not significantly increased in GT/TT variant carriers compared to GG ones. The patients with the T allele tended to respond worse to immunomodulatory treatment and more frequently received antifibrotic drugs. In conclusions: The frequency of MUC5B polymorphism in HP patients is high. The T allele may indicate a worse disease course, worse immunomodulatory treatment response, and earlier need for antifibrotic treatment.

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2023-04-14 | 5-methyladenosine regulators play a crucial role in development of chronic hypersensitivity pneumonitis and idiopathic pulmonary fibrosis.

5-methyladenosine (m5C) modification regulates gene expression and biological functions in oncologic areas. However, the effect of m5C modification in chronic hypersensitivity pneumonitis (CHP) and idiopathic pulmonary fibrosis (IPF) remains unknown. Expression data for 12 significant m5C regulators were obtained from the interstitial lung disease dataset. Five candidate m5C regulators, namely tet methylcytosine dioxygenase 2, NOP2/Sun RNA methyltransferase 5, Y-box binding protein 1, tRNA aspartic acid methyltransferase 1, and NOP2/Sun RNA methyltransferase 3 were screened using random forest and nomogram models to predict risks of pulmonary fibrosis. Next, we applied the consensus clustering method to stratify the samples with different m5C patterns into two groups (cluster A and B). Finally, we calculated immune cell infiltration scores via single-sample gene set enrichment analysis, then compared immune cell infiltration, related functions as well as the expression of programmed cell death 1 (PD-1, PDCD1) and programmed death protein ligand-1 (PD-L1, CD274) between the two clusters. Principal component analysis of m5C-related scores across the 288 samples revealed that cluster A had higher immune-related expression than B. Notably, T helper cell (Th) 2 type cytokines and Th1 signatures were more abundant in clusters A and B, respectively. Our results suggest that m5C is associated with and plays a crucial role in development of pulmonary fibrosis. These m5C patterns could be potential biomarkers for identification of CHP and IPF, and guide future development of immunotherapy or other new drugs strategies for pulmonary fibrosis.

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2023-02-23 | The protective role of HMGB1 in affecting the balance between autophagy and pyroptosis to maintain neutrophils homeostasis during β-glucan-induced mice lung inflammation.

Fungal contamination is omnipresent, and inhalation of fungi-contaminated organic dust leads to hypersensitivity pneumonitis (HP), in which neutrophils played a pivotal role. Existing studies have suggested that cell homeostasis is crucial for the pathogenesis of the inflammatory disease. Although HMGB1 has been shown to contribute to suppressing HP, there is a lack of studies on its mechanisms, especially the regulation of neutrophil homeostasis. This study aims to investigate how HMGB1 regulates neutrophil function by affecting neutrophil homeostasis, and then affects lung inflammation induced by β-glucan, the exposure marker of fungi. Our results showed that deficient HMGB1 led to neutrophil death by disrupting the balance between autophagy and pyroptosis after β-glucan treatment. And HMGB1 deficiency exacerbated the β-glucan-induced lung inflammation and neutrophil dysfunction both in vivo and in vitro. Furthermore, HMGB1 contributed to remodeling neutrophil function by restricting autophagy and aggravating pyroptosis β-glucan exposure. Our funding suggested that HMGB1 deficiency could break the balance between autophagy and pyroptosis towards pyroptosis to cause neutrophil dysfunction during the exacerbated inflammatory response, which provides insights into the pathogenesis of HP and the potential biological targets for its treatment. DATA AVAILABILITY: The datasets used during the current study are available from the corresponding author on reasonable request.

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2022-07-14 | Relevance of RNA N6-Methyladenosine Regulators for Pulmonary Fibrosis: Implications for Chronic Hypersensitivity Pneumonitis and Idiopathic Pulmonary Fibrosis

N6-methyladenosine (m6A) modification plays a pivotal role in post-transcriptionally regulating gene expression and biological functions. Nonetheless, the roles of m6A modification in the regulation of chronic hypersensitivity pneumonitis (CHP) and idiopathic pulmonary fibrosis (IPF) remain unclear. Twenty-two significant m6A regulators were selected from differential gene analysis between the control and treatment groups from the GSE150910 dataset. Five candidate m6A regulators (insulin-like growth factor binding protein 2, insulin-like growth factor binding protein 3, YTH domain-containing protein 1, zinc finger CCCH domain-containing protein 13, and methyltransferase-like 3) were screened by the application of a random forest model and nomogram model to predict risks of pulmonary fibrosis. The consensus clustering method was applied to divide the treatment samples into two groups with different m6A patterns (clusters A and B) based on the 22 m6A regulators. Our study performed principal component analysis to obtain the m6A-related score of the 288 samples to quantify the two m6A patterns. The study reveals that cluster A was linked to T helper cell (Th) 2-type cytokines, while the immune infiltration of Th1 cytokines was higher in cluster B. Our results suggest that m6A cluster A is likely related to pulmonary fibrosis, indicating m6A regulators play notable roles in the occurrence of pulmonary fibrosis. The m6A patterns could be considered as biomarkers to identify CHP and IPF, which will be helpful to develop immunotherapy strategies for pulmonary fibrosis in the future.

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